Contact pathway in surgical and transcatheter aortic valve replacement

Abstract

Background: Aortic valve replacement is the gold standard treatment for severe symptomatic aortic stenosis, but thrombosis of bioprosthetic valves (PVT) remains a concern.

Objective: To analyze the factors involved in the contact pathway during aortic valve replacement and to assess their impact on the development of thromboembolic complications.

Methods: The study was conducted in 232 consecutive patients who underwent: transcatheter aortic valve replacement (TAVR, N = 155), and surgical valve replacement (SAVR, N = 77) (MUVITAVI project). Demographic and clinical data, outcomes including a combined end point (CEP) of thrombotic events, and imaging controls were recruited. Samples were collected 24 h before and 48 h after valve replacement. FXII, FXI and (pre)kallikrein were evaluated by Western Blot and specific ELISA with nanobodies.

Results: The CEP of thrombotic events was reached by 19 patients: 13 patients presented systemic embolic events and 6 patients subclinical PVT. Valve replacement did not cause FXII activation or generation of kallikrein. There was a significant reduction of FXI levels associated with the procedure, which was statistically more pronounced in SAVR than in TAVR. Cases with reductions of FXI below 80% of basal values had a lower incidence of embolic events during the procedure than patients in whom FXI increased above 150%: 2.7 vs. 16.7%; p: 0.04.

Conclusion: TAVR or SAVR did not significantly activate the contact pathway. A significant reduction of FXI, was observed, particularly in SAVR, associated with lower incidence of thrombotic events. These results encourage evaluating the usefulness and safety of FXI-directed antithrombotic treatments in these patients.

Keywords: aortic valve replacement; contact pathway; factor XI; factor XII; kallikrein; thrombosis.

FIGURE 1

Scheme of the contact pathway and its involvement in coagulation, inflammation and complement system. Surgical (SAVR) or transcatheter (TAVR) aortic valve is illustrated as a potential trigger of FXII autoactivation. Dashed red arrows indicate inhibition; green arrows activation; yellow arrows activation by thrombin. APC, activated protein C; Ki, Kininogen; PK, prekallikrein; K, kallikrein; BK, bradykinin; TAFI, thrombin activable fibrinolysis inhibitor; Fg, fibrinogen; C1-inh, C1-inhibitor; uPAR, urokinase-type plasminogen; TF, Tissue Factor.

FIGURE 2

Plasma FXII (A), Pre(Kallikrein) (B), and FXI (C) detected by Western Blot after SDS-PAGE in representative samples of patients underwent TAVR or SAVR. The samples pre and post-procedure are indicated. Zymogens are pointed by black arrows, while activated forms are pointed by red arrows. As control of activation, plasma from a pool of 100 healthy blood donors was treated with silica.

FIGURE 3

Levels of FXIIa-C1 Inhibitor complexes in pre- and post-procedure samples. Values, referenced as percentages of kaolin-full activated reference pool plasma generated 100 healthy subjects, were determined by a specific ELISA using nanobodies. ns: p > 0.05.

FIGURE 4

FXIa levels in patient samples pre and post-procedure. (A) Representative Western blot of plasma samples of patients pre- and post- procedure. As control, plasma from a healthy subject was also evaluated without and after full activation with kaolin; (B) FXIa-C1 inhibitor complexes quantified by ELISA using nanobodies. As standards, a basal sample, and dilutions of fully kaolin-activated plasma of a pool of 100 healthy control subjects were used.

FIGURE 5

FXI levels determined by a chromogenic method after full activation with kaolin in pre- and post-procedure samples. Values were represented as% of a reference pool of plasma from 100 healthy subjects. **p < 0.01.

FIGURE 6

Antithrombin activity in patients underwent transcatheter aortic valve replacement. (A) Anti-FXa activity. (B) Thrombin-Antithrombin complexes quantified by ELISA. (C) Plasma antithrombin detected by Western blot. Representative samples are shown.